Proposed experiments will examine the effect of gonadal hormones and aging on cholinergic cell body areas of the basal forebrain and on their projection sites in the cerebral cortex and limbic brain. Microanatomical sampling and biochemical analysis will be utilized to measure activity of the enzymes of acetylcholine metabolism, choline acetyltransferase and acetylcholinesterase, in these discrete brain areas. Previous work has shown that the gonadal hormone estradiol affects the activity of these enzymes in the diagonal band nuclei of the forebrain. In these studies, estradiol will be given to gonadectomized male and female rats and effects on the enzymes in the diagonal band nuclei and other forebrain nuclei and their projection sites will be determined. Male and female rats will also be gonadectomized on a long term basis and effects on the enzymes measured. Activities in sexually mature males and females will be compared with aged (24 months) males and females. Results of the experiments will be compared and may indicate to what extent age dependent changes in enzyme activities include gonadal hormones as one of the determinants. Recent evidence suggests that loss of basal forebrain cholinergic cell bodies may be responsible for plaques and tangles which are present in the cerebral cortex in Alzheimer's disease. Proposed studies may indicate whether gonadal hormones acting in basal forebrain cells could be one of the factor(s) contributing to the etiology of Alzheimer's disease. The studies may also provide a basis for further work relevant to the use of gonadal hormone therapy in Alzheimer's disease.